This a 10-year competitive renewal of a Merit Award that builds upon a total of 25 years of previously funded research. Over this period we have identified the role of glutamate transmission in the nucleus accumbens as critical for behavioral sensitization and the reinstatement of cocaine seeking in an animal model of relapse. Both pre- and postsynaptic cocaine-induced neuroadaptations have been discovered. Recently, the diverse array of cocaine induced changes discovered in our laboratory and by others have been amalgamated into the glutamate homeostasis hypothesis of addiction wherein dysregulation in the balance between synaptic and nonsynaptic glutamate release and uptake is proposed to be critical in the vulnerability to relapse. Supporting this hypothesis, restoring glutamate homeostasis with N-acetylcysteine (NAC) has been shown to produce enduring protection against reinstated cocaine seeking, and appears to normalize many cocaine-induced changes in synaptic plasticity. In the aim #1 of the present proposal we will further characterize the behavioral protection by NAC, evaluating dose-response curves and duration of action after discontinuing NAC. The remaining 3 aims focus on our recent findings that NAC produces an enduring restoration in measures of glutamate homeostasis and metabotropic glutamate receptor (mGluR) dependent neuroplasticity in the nucleus accumbens. Accordingly, aim #2 evaluates the enduring restoration by NAC in the level and function of nonsynaptic glutamate release via the cystine-glutamate exchanger and glial glutamate uptake. Aim #3 determines if daily NAC restores classic measures of neuroplasticity, including longterm potentiation, longterm depression and dendritic spine morphology. Finally, aim #4 examines the effects of daily NAC on signaling via presynaptic mGluR2/3 and postsynaptic signaling on mGluR5. Moreover, in this aim it will be determined if mGluR agonists and antagonists can promote or inhibit the capacity of daily NAC to normalize glutamate homeostasis and synaptic plasticity in the nucleus accumbens. PUBLIC HEALTH RELEVANCE: Cocaine addiction is associated with impaired neuroplasticity in the prefrontal cortico-striatal brain circuitry that is important for guiding adaptive behavior. The premise of this proposal is that it is possible to repair this corticostriatal deficit and thereby ameliorate the vulnerability to relapse. Accordingly, we propose to characterize the ability of daily N-acetylcysteine treatment to produce enduring protection from the reinstatement of cocaine seeking, and associate this protection with restoring neuroplasticity.